By David N. Leff

Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.

Swapping one amino acid for another successfully treated the untreatable stage of a disease that kills 32,000 men a year in the U.S. alone. To be sure, the correction occurred in rats, but its strategy is aimed at metastatic prostate cancer in humans.

Prostate cancer (PC) is the commonest malignancy of men. It starts out in its elderly patients as a relatively manageable complaint. As long as the prostate gland's cancerous cells are contained within the organ's capsule, or shell, surgical removal of the organ affords outright cure. However, by the time urological examination confirms the diagnosis of cancer, 60 percent of those malignant cells have escaped, and fan out to metastasize other parts of the patient's body - mainly the lungs.

At this point, the androgen hormone testosterone powers the prostate metastasis, similar to the estrogen that drives post-mastectomy breast cancer. The last-resort treatment is removing the testicles, the main source of the androgen. However, this testosterone ablation provides only temporary control of the metastatic prostate cells, which in about 18 months inevitably develop independence of the hormonal therapy - something like drug resistance in bacteria - and the metastases resume their lethal spread, this time unimpeded.

"Since androgen withdrawal is currently the only effective form of systemic therapy for metastatic prostate cancer," cell biologist Donna Livant pointed out, "the appearance of androgen-independent clones of tumor cells means that there is no effective curative therapy for patients thereafter. Thus, new therapies to treat invasive or metastatic prostate cancer are necessary."

Livant, of the University of Michigan in Ann Arbor, is lead author of a report in the current issue of the twice-monthly journal Cancer Research, dated Jan. 15, 2000. Its title: "Anti-invasive, antitumorigenic, and antimetastatic activities of the PHSCN sequence in prostate carcinoma." That PHSCN is the key code word in the therapeutic strategy her paper describes. Its five letters denote the amino-acid peptide that decisively checked advanced metastatic PC in tumor-bearing rats.

Specifically, the sequence denotes the amino-acid chain proline-histidine-serine-cysteine-asparagine, occurring in fibronectin, a common blood protein. The novel peptide's antitumor activity, as the paper recounts, depended on replacing an arginine moiety with the cysteine.

When tissue is damaged, Livant explained, "fibronectin at the injury site fragments, and these fragments bind to nearby fibronectin receptors, which stimulate them to invade and repair the tissue. "Cancer is the price we pay," she observed, "for our body's ability to heal from wounds." She and her co-authors isolated the one peptide in fibronectin, namely, PHSRN, that triggered the invasion process.

In substituting cysteine for arginine (R) in the PHSRN sequence, they "speculated that cysteine might interact with the PHSRN-binding pocket of the fibronectin receptor in such a way as to block binding and prevent triggering cancer cell invasion." It panned out accordingly.

The team injected lab rats with 100,000 cells at a time from a naturally occurring, metastatic rat PC cell line, which can kill an animal in 25 days. Experimental rats then got thrice-weekly injections of the new PHSCN cysteine derivative. Sixteen days later, the mean diameter of tumors in treated animals was less than half a millimeter, vs. 1.8 centimeters in controls - a 2,000-times larger volume. In a second experiment, designed closer to human PC treatment, rats that first received PHSCN 24 hours after surgery developed 99.9 percent fewer visible lung metastases than those treated with surgery alone.

"If future studies show the peptide works as well in people," Livant concluded, "it could be the basis for a new approach to cancer therapy."

Two Esoteric Dermatological Diseases Share Newly Found Gene, With Therapeutic Potential

On an unrelated front, single amino-acid substitutions figured in six of 21 gene abnormalities encountered in 61 American and Japanese families afflicted with Hailey-Hailey disease (HHD). This hereditary disorder of aberrant calcium levels in epidermal keratinocytes (skin cells) is marked by blistering and erosions. Its autosomal dominant familial inheritance pattern arises from a gene discovered by research dermatologists at the University of California, San Francisco. Their report in the January 2000 issue of Nature Genetics is titled: "Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease."

The gene makes a pump that transports calcium into the Golgi apparatus, a cellular way station where proteins marked for secretion (export) are processed. The abnormal calcium metabolism in HHD sufferers weakens the connections holding their skin cells together, causing the blisters. A second dermatological defect, involving a different calcium pump, is Darier-White disease, in which the skin develops foul-smelling scaly bumps.

The paper concludes: "Distinguishing which mechanisms connect the ATP2C1 defect to the acantholysis [separation of individual keratinocytes from their neighbors] should aid therapeutic attempts to treat the blisters."

Scripps Scientists Contrive Lego-Like Modular Genomic Construct That Turns Genes On, Off

DNA expression is frequently analogized to computer functions, but now scientists at the Scripps Research Institute in La Jolla, Calif., announce, "In essence, we have created an operating system for genomes." Their "Early Edition" article in the Proceedings of the National Academy of Sciences, released Jan. 28, 2000, is titled: "Positive and negative regulation of endogenous genes by designed transcription factors." It describes a method of producing and combining proteins as modular building blocks - akin to a child's Lego set - that switch genes on and off on demand.

"The importance of this work cannot be overestimated," commented the institute's president, Richard Lerner. "Its goal is to develop a new class of therapeutic proteins that can inhibit or enhance synthesis of proteins, providing a new strategy for fighting diseases of either somatic or viral origin."

The paper's co-authors are presently building a protein that binds to the Huntington's disease gene, devising a method for correcting sickle cell anemia, and constructing modular proteins to check the spread of HIV. They point out, "Insulin production, for example, could potentially be controlled in this fashion."